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Intragenic DNA methylation prevents spurious transcription initiation

Author

Listed:
  • Francesco Neri

    (Human Genetics Foundation (HuGeF)
    Leibniz Institute on Aging – Fritz Lipmann Institute (FLI))

  • Stefania Rapelli

    (Università di Torino)

  • Anna Krepelova

    (Human Genetics Foundation (HuGeF)
    Università di Torino)

  • Danny Incarnato

    (Human Genetics Foundation (HuGeF))

  • Caterina Parlato

    (Human Genetics Foundation (HuGeF))

  • Giulia Basile

    (Human Genetics Foundation (HuGeF))

  • Mara Maldotti

    (Human Genetics Foundation (HuGeF)
    Università di Torino)

  • Francesca Anselmi

    (Human Genetics Foundation (HuGeF)
    Università di Torino)

  • Salvatore Oliviero

    (Human Genetics Foundation (HuGeF)
    Università di Torino)

Abstract

In mammals, DNA methylation occurs mainly at CpG dinucleotides. Methylation of the promoter suppresses gene expression, but the functional role of gene-body DNA methylation in highly expressed genes has yet to be clarified. Here we show that, in mouse embryonic stem cells, Dnmt3b-dependent intragenic DNA methylation protects the gene body from spurious RNA polymerase II entry and cryptic transcription initiation. Using different genome-wide approaches, we demonstrate that this Dnmt3b function is dependent on its enzymatic activity and recruitment to the gene body by H3K36me3. Furthermore, the spurious transcripts can either be degraded by the RNA exosome complex or capped, polyadenylated, and delivered to the ribosome to produce aberrant proteins. Elongating RNA polymerase II therefore triggers an epigenetic crosstalk mechanism that involves SetD2, H3K36me3, Dnmt3b and DNA methylation to ensure the fidelity of gene transcription initiation, with implications for intragenic hypomethylation in cancer.

Suggested Citation

  • Francesco Neri & Stefania Rapelli & Anna Krepelova & Danny Incarnato & Caterina Parlato & Giulia Basile & Mara Maldotti & Francesca Anselmi & Salvatore Oliviero, 2017. "Intragenic DNA methylation prevents spurious transcription initiation," Nature, Nature, vol. 543(7643), pages 72-77, March.
  • Handle: RePEc:nat:nature:v:543:y:2017:i:7643:d:10.1038_nature21373
    DOI: 10.1038/nature21373
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    Cited by:

    1. Zhaoyun Ding & Ting Cai & Jupei Tang & Hanxiao Sun & Xinyi Qi & Yunpeng Zhang & Yan Ji & Liyun Yuan & Huidan Chang & Yanhui Ma & Hong Zhou & Li Li & Huiming Sheng & Ju Qiu, 2022. "Setd2 supports GATA3+ST2+ thymic-derived Treg cells and suppresses intestinal inflammation," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    2. Omid Omrani & Anna Krepelova & Seyed Mohammad Mahdi Rasa & Dovydas Sirvinskas & Jing Lu & Francesco Annunziata & George Garside & Seerat Bajwa & Susanne Reinhardt & Lisa Adam & Sandra Käppel & Nadia D, 2023. "IFNγ-Stat1 axis drives aging-associated loss of intestinal tissue homeostasis and regeneration," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    3. Romain O. Georges & Hugo Sepulveda & J. Carlos Angel & Eric Johnson & Susan Palomino & Roberta B. Nowak & Arshad Desai & Isaac F. López-Moyado & Anjana Rao, 2022. "Acute deletion of TET enzymes results in aneuploidy in mouse embryonic stem cells through decreased expression of Khdc3," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    4. Yongjun Piao & Wanxue Xu & Kwang Ho Park & Keun Ho Ryu & Rong Xiang, 2021. "Comprehensive Evaluation of Differential Methylation Analysis Methods for Bisulfite Sequencing Data," IJERPH, MDPI, vol. 18(15), pages 1-15, July.
    5. Andrea Lauria & Guohua Meng & Valentina Proserpio & Stefania Rapelli & Mara Maldotti & Isabelle Laurence Polignano & Francesca Anselmi & Danny Incarnato & Anna Krepelova & Daniela Donna & Chiara Levra, 2023. "DNMT3B supports meso-endoderm differentiation from mouse embryonic stem cells," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    6. Theodore Sakellaropoulos & Catherine Do & Guimei Jiang & Giulia Cova & Peter Meyn & Dacia Dimartino & Sitharam Ramaswami & Adriana Heguy & Aristotelis Tsirigos & Jane A. Skok, 2024. "MethNet: a robust approach to identify regulatory hubs and their distal targets from cancer data," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    7. Chirag Nepal & Jesper B. Andersen, 2023. "Alternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    8. Li He & Huan Huang & Mariem Bradai & Cheng Zhao & Yin You & Jun Ma & Lun Zhao & Rosa Lozano-Durán & Jian-Kang Zhu, 2022. "DNA methylation-free Arabidopsis reveals crucial roles of DNA methylation in regulating gene expression and development," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    9. Jiankang Wang & Masashige Bando & Katsuhiko Shirahige & Ryuichiro Nakato, 2022. "Large-scale multi-omics analysis suggests specific roles for intragenic cohesin in transcriptional regulation," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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